PMID- 30620390
OWN - NLM
STAT- MEDLINE
DCOM- 20200114
LR  - 20210629
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 125
IP  - 8
DP  - 2019 Apr 15
TI  - Distinct genome-wide methylation patterns in sporadic and hereditary 
      nonfunctioning pancreatic neuroendocrine tumors.
PG  - 1247-1257
LID - 10.1002/cncr.31930 [doi]
AB  - BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or 
      progression. There are scant data on the genome-wide methylation pattern of 
      nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and 
      hereditary NFPanNETs. METHODS: Thirty-three tissue samples were analyzed: they 
      included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), 
      and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well 
      as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation 
      profiling was performed with the Infinium MethylationEPIC BeadChip assay and was 
      analyzed with R-based tools. RESULTS: In unsupervised hierarchical clustering, 
      sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in 
      a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated 
      CpG sites in comparison with sporadic and VHL-related tumor groups. 
      Differentially methylated region analysis confirmed the higher rate of 
      hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of 
      gene expression data for the same tumor samples, downregulated gene expression 
      was found in most genes that were hypermethylated. In a CpG island methylator 
      phenotype analysis, 3 genes were identified and confirmed to have downregulated 
      gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs 
      and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 
      (RBM47) in MEN1-related NFPanNETs. CONCLUSIONS: MEN1 NFPanNETs have a higher rate 
      of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity 
      between the pathways enriched in a methylation analysis of known genes involved 
      in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the 
      pathogenesis of NFPanNETs.
CI  - (c) 2019 American Cancer Society.
FAU - Tirosh, Amit
AU  - Tirosh A
AUID- ORCID: 0000-0003-3794-9634
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
AD  - Endocrine Oncology Bioinformatics Lab, Sheba Medical Center, Sackler Faculty of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Mukherjee, Sanjit
AU  - Mukherjee S
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Lack, Justin
AU  - Lack J
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Gara, Sudheer Kumar
AU  - Gara SK
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Wang, Sophie
AU  - Wang S
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Quezado, Martha M
AU  - Quezado MM
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Keutgen, Xavier M
AU  - Keutgen XM
AUID- ORCID: 0000-0002-4627-3560
AD  - Division of Surgical Oncology, Department of Surgery, Rush University Medical 
      Center, Chicago, Illinois.
FAU - Wu, Xiaolin
AU  - Wu X
AD  - Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick 
      National Laboratory for Cancer Research, Frederick, Maryland.
FAU - Cam, Maggie
AU  - Cam M
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Kumar, Suresh
AU  - Kumar S
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Patel, Dhaval
AU  - Patel D
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Nilubol, Naris
AU  - Nilubol N
AD  - Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland.
FAU - Tyagi, Monica Varun
AU  - Tyagi MV
AD  - Department of Surgery, Stanford University, Stanford, California.
AD  - Stanford Cancer Institute, Stanford University, Stanford, California.
FAU - Kebebew, Electron
AU  - Kebebew E
AUID- ORCID: 0000-0001-5254-1456
AD  - Department of Surgery, Stanford University, Stanford, California.
AD  - Stanford Cancer Institute, Stanford University, Stanford, California.
LA  - eng
GR  - ZIA BC011275/ImNIH/Intramural NIH HHS/United States
GR  - ZIA BC011286/ImNIH/Intramural NIH HHS/United States
GR  - ZIA BC011275/BC/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20190108
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CDCA7L protein, human)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RBM47 protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (SFRP5 protein, human)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*genetics
MH  - Carcinoma, Neuroendocrine/*classification/genetics
MH  - CpG Islands
MH  - *DNA Methylation
MH  - Down-Regulation
MH  - Epigenesis, Genetic
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Pancreatic Neoplasms/*classification/genetics
MH  - Proto-Oncogene Proteins/genetics
MH  - RNA-Binding Proteins/*genetics
MH  - Repressor Proteins/*genetics
MH  - Unsupervised Machine Learning
MH  - Von Hippel-Lindau Tumor Suppressor Protein/genetics
MH  - Whole Genome Sequencing/*methods
PMC - PMC8237345
MID - NIHMS1001016
OTO - NOTNLM
OT  - DNA methylation
OT  - multiple endocrine neoplasia type 1 (MEN1)
OT  - nonfunctioning
OT  - pancreatic neuroendocrine tumor
OT  - von Hippel-Lindau (VHL)
COIS- The authors declare that they have nothing to disclose.
EDAT- 2019/01/09 06:00
MHDA- 2020/01/15 06:00
PMCR- 2021/06/28
CRDT- 2019/01/09 06:00
PHST- 2018/09/04 00:00 [received]
PHST- 2018/07/01 00:00 [revised]
PHST- 2018/09/28 00:00 [accepted]
PHST- 2019/01/09 06:00 [pubmed]
PHST- 2020/01/15 06:00 [medline]
PHST- 2019/01/09 06:00 [entrez]
PHST- 2021/06/28 00:00 [pmc-release]
AID - 10.1002/cncr.31930 [doi]
PST - ppublish
SO  - Cancer. 2019 Apr 15;125(8):1247-1257. doi: 10.1002/cncr.31930. Epub 2019 Jan 8.